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Tenofovir disoproxil fumarate safety for women and their infants during pregnancy and breastfeeding

Mofenson, Lynne M.; Baggaley, Rachel C.; Mameletzis, Ioannis

doi: 10.1097/QAD.0000000000001313
CLINICAL SCIENCE

Objectives: Pregnant/lactating women in some sub-Saharan Africa settings are at substantial risk of HIV acquisition and could benefit from preexposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF), but safety data in pregnancy/lactation are limited.

Design: Systematic data review through August 2016.

Methods: We reviewed research reports/conference abstracts with maternal/child adverse outcome data in HIV-infected and HIV-uninfected pregnant/lactating women receiving TDF alone or in combination with other drugs compared with non-TDF regimens.

Results: In total, 26 articles in HIV-infected and seven in HIV-uninfected women were identified. No statistically significant differences were observed between TDF and comparison non-TDF regimens in pregnancy incidence, stillbirth/pregnancy loss, preterm delivery less than 37 weeks, low birth weight <2500/<1500 g, small for gestational age, birth defects, or infant (>14 days) or maternal mortality. One study reported significantly higher very preterm delivery (<34 weeks) and neonatal mortality with TDF versus non-TDF antiretroviral therapy (ART), but no significant difference between TDF ART and zidovudine/single-dose nevirapine. Most studies report normal infant linear growth; one study showed slightly lower, and one higher 1-year length-for-age z-score in TDF ART-exposed infants. No significant differences were reported in abnormal laboratory values or bone markers between TDF and non-TDF-exposed infants in four studies. Lower maternal bone mineral density was observed at 74 weeks postpartum in breastfeeding women on TDF ART compared with no ART in one study.

Conclusion: Given available safety data, there does not appear to be a safety-related rationale for prohibiting PrEP during pregnancy/lactation or for discontinuing PrEP in HIV-uninfected women receiving PrEP who become pregnant and are at continuing risk of HIV acquisition.

aElizabeth Glaser Pediatric AIDS Foundation, Washington DC, USA

bWorld Health Organization, Geneva, Switzerland.

Correspondence to Lynne M. Mofenson, Elizabeth Glaser Pediatric AIDS Foundation, 1140 Connecticut Avenue, Suite 200, Washington DC 20036, USA. Tel: +1 301 236 9319; e-mail: mofensol@gmail.com

Received 8 September, 2016

Revised 11 October, 2016

Accepted 19 October, 2016

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Background

Preexposure prophylaxis (PrEP) with daily oral tenofovir disoproxil fumarate (TDF) or coformulated TDF/emtricitabine (TDF/FTC) has been shown to be effective in prevention of HIV acquisition in men who have sex with men (MSM), heterosexual men and women, and persons who inject drugs [1,2]. In 2015, the WHO made a strong recommendation for the use of oral PrEP as ‘…an additional prevention choice for people at substantial risk of HIV infection, as part of combination HIV prevention approaches…’ [3]. ‘Substantial risk’ was defined as HIV incidence of 3/100 person-years or higher in the absence of PrEP.

Based on the available data, pregnant and lactating women residing in high HIV burden settings in sub-Saharan Africa are at substantial risk of HIV acquisition. In a systematic review and meta-analysis containing data from 19 cohorts representing 22 803 total woman-years, the pooled HIV incidence during pregnancy/postpartum was 3.8/100 woman-years (4.7 and 2.9/100 woman-years during pregnancy and postpartum, respectively); the pooled cumulative incidence in African countries was 3.6% compared with 0.3% in non-African countries [4]. Additionally, in high-resource countries with lower HIV incidence among women, PrEP has been proposed as an additional prevention intervention during the periconception period to prevent transmission from an HIV infected to uninfected partner in serodiscordant couples desiring pregnancy [5]. However, concerns and uncertainty about safety of PrEP during pregnancy and lactation on the part of public health authorities and healthcare providers has affected large-scale PrEP implementation among women of child-bearing age. There is a critical need to examine PrEP safety among HIV-uninfected pregnant and breastfeeding women and their infants, but safety data specific to the HIV-uninfected population are limited. PrEP efficacy trials excluded pregnant women from enrollment and conducted monthly pregnancy testing, with discontinuation of study drug as soon as pregnancy was detected, so provide only limited data on early first trimester exposure. We performed a systematic review of available data on safety of TDF in pregnancy and breastfeeding in HIV-infected and HIV-uninfected women and their infants.

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Methods

We included published primary research reports in English on HIV-infected or HIV-uninfected women who received oral TDF alone or in combination with other drugs during pregnancy or breastfeeding. We focused on cohort studies or trials that compared maternal and child adverse outcomes among women receiving TDF versus not receiving TDF during pregnancy or breastfeeding.

A comprehensive systematic search of the literature through August 2016 included PubMed (key search terms: tenofovir and pregnancy; tenofovir and breastfeeding; tenofovir and breast milk); references from prior systematic reviews; conference abstracts from 2014 to 2016 from the Conference on Retroviruses and Opportunistic Infections, the International AIDS Conference, and the International Workshop on HIV Pediatrics; a search of clinicialtrials.gov; and communication with the manufacturer (Gilead Sciences, Foster City, California, USA).

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Role of the funding source

WHO funded this study and their staff (R.C.B. and I.M.) contributed to data interpretation and writing of the report. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

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Results

Study characteristics

Study identification and selection is shown in Fig. 1. The literature search identified 230 unique studies. Screening of title/abstract identified 157 studies for review; 124 were excluded because of lack of relevance, absence of pregnancy/safety outcome or comparative data, or were in-vitro/animal or vaginal TDF gel studies. This left 33 studies published between 2011 and 2016 with comparative data: 26 studies on TDF antiretroviral therapy (ART) in HIV-infected women (20 comparing TDF ART with non-TDF ART, two comparing TDF ART with zidovudine/single-dose nevirapine [ZDV/sdNVP] or no ART, and four comparing different TDF ART durations during pregnancy) [6–31], five on TDF use in hepatitis B virus (HBV) monoinfected women [32–36], and two on HIV-uninfected women from PrEP trials [37,38].

Fig. 1

Fig. 1

Table 1 shows study characteristics. Most were prospective cohorts. Five were randomized clinical trials: two in HIV-infected women [one trial, Promoting Maternal-Infant Survival Everywhere (PROMISE), included separate reports on the Antepartum and Postpartum trial components and two substudies] and three in HIV-uninfected women (one HBV monoinfection and two PrEP trials) [7,19,25,30,31,36–38]. The HIV studies included six from the United States [8,11,12,15–17], two from Italy [6,10], one each from France [13] and the Netherlands [27], one international registry [20], and 15 studies from Africa (Botswana, Kenya, Uganda, Malawi, South Africa, and five multicountry studies) [7,9,14,18,19,21–26,28–31]. HBV studies included one each from Australia, Canada, China, Taiwan, and Turkey [32–36]. Both PrEP studies were multicountry studies, one in Kenya/Uganda and one in South Africa/Uganda/Zimbabwe [37,38].

Table 1

Table 1

Table 1

Table 1

Table 1

Table 1

Table 1

Table 1

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Pregnancy incidence

Pregnancy incidence was evaluated in HIV-infected women receiving ART in one study and in HIV-uninfected women who became pregnant while enrolled in two PrEP trials (Table 2 ). There was no significant difference in pregnancy incidence between women receiving TDF ART versus non-TDF ART or receiving TDF or TDF/FTC PrEP versus placebo [9,37,38].

Table 2

Table 2

Table 2

Table 2

Table 2

Table 2

Table 2

Table 2

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Stillbirth/pregnancy loss

Four studies reported on stillbirth (≥22-week gestation) among HIV-infected women receiving TDF ART, non-TDF ART or ZDV/sdNVP [7,19,21,22]. No significant difference in stillbirths was observed between women receiving TDF ART versus non-TDF ART in any study. In one study, stillbirths were higher in women receiving ART (both TDF ART and non-TDF ART) compared with ZDV/sdNVP (P = 0.041 and P = 0.002, respectively) but similar between ART regimens (P = 0.77) [21]. A separate study did not find a significant difference in stillbirth among women receiving ART versus ZDV/sdNVP [19]. Another study compared stillbirth stratified by time of ART initiation (preconception versus during pregnancy), with no significant differences between TDF ART versus non-TDF ART regardless of time of initiation [22].

In HIV-uninfected women, stillbirth and pregnancy loss/spontaneous abortion (<22-week gestation) rates were available from five studies in HBV-monoinfected women [32–36]. Rates were low (0–4.2%) and did not differ between HBV-infected women receiving TDF, lamivudine (3TC), or no treatment. Data were available from two PrEP clinical trials [Partners PrEP and Vaginal and Oral Interventions to Control the HIV Epidemic (VOICE)] where women became pregnant after enrollment [37,38]. Pregnancy tests were done monthly in these studies and PrEP discontinued if pregnancy was diagnosed. Pregnancy losses were high (15–43%), likely because repeated pregnancy testing detected early pregnancy losses that would otherwise not have been recognized. However, pregnancy losses were not significantly different between women receiving TDF or TDF/FTC PrEP compared with placebo [37,38]. Stillbirth rates were 2–5% and not significantly different between regimens [38].

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Preterm delivery

Preterm delivery (PTD; <37-week gestation) was reported in six studies in HIV-infected women [7,11,19,21–23] (Table 2 ). PTD was not significantly different among women receiving TDF ART versus non-TDF ART (five studies) or ZDV/sdNVP (two studies). In the PROMISE trial, women randomized to either TDF ART or non-TDF ART had nonsignificantly higher PTD rates (18.5–19.7%) than women randomized to ZDV/sdNVP (13.5%) [19]. One study compared TDF ART and non-TDF ART stratified by time of ART initiation, with no significant difference between TDF and non-TDF ART regardless of time of initiation [22]. An additional study compared PTD in women receiving only TDF ART by time of initiation, reporting no difference between women starting TDF ART preconception versus during pregnancy [23].

Very preterm delivery (VPTD; <34-week gestation) was reported in two studies in HIV-infected women [19,22]. In the PROMISE trial, although VPTD was significantly higher in women randomized to TDF ART versus non-TDF ART (6.0 versus 2.9%, respectively, P = 0.036), it was not significantly different between women randomized to TDF ART versus ZDV/sdNVP (3.2%, P = 0.10) [19]. In the other study, VPTD rates were not significantly different between women receiving TDF ART versus non-TDF ART (10 versus 12%, respectively) [22].

PTD data in HIV-uninfected women were available from six studies [33–38]; HIV-uninfected women had lower PTD rates (0–8.3%) than HIV-infected women (7.2–31%). PTD in HBV-monoinfected women did not differ between women receiving TDF, 3TC or no treatment, or in the HIV-uninfected women in PrEP studies randomized to TDF and TDF/FTC PrEP versus placebo.

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Low birth weight

Six studies in HIV-infected women reported on low birth weight (LBW) less than 2500 g [7,8,18,19,21,23] (Table 2 ). All studies reported no significant difference in LBW between women receiving TDF ART versus non-TDF ART. In the PROMISE trial, LBW was significantly higher in women randomized to TDF ART (16.9%) and non-TDF ART (20.4%) compared with ZDV/sdNVP (8.9%), but LBW was not significantly different between TDF ART versus non-TDF ART (P = 0.303) [19]. In a nonrandomized study, LBW was similar in women receiving TDF ART (13.5%), non-TDF ART (15.3%), and ZDV/sdNVP (10.0%) [21]. One study compared women receiving TDF ART by time of initiation, with no difference between women starting TDF ART preconception compared with during pregnancy [23].

Data on very LBW (VLBW) less than 1500 g were available from the PROMISE trial; VLBW rates were nonsignificantly higher in women randomized to TDF ART (2.0%) than non-TDF ART (0.6%, P = 0.17) or ZDV/sdNVP (0.3%, P = 0.063) [19].

LBW rates in HBV-monoinfected women (0–4.7%) were much lower than observed for HIV-infected women (10–20.4%), and not significantly different among HBV-monoinfected women receiving TDF, 3TC, or no treatment [32,33].

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Small for gestational age

Four studies in HIV-infected women reported on small for gestational age (SGA) infants [8,21–23] (Table 2 ). SGA was not significantly different between women receiving TDF ART versus non-TDF ART (two studies) [8,21] or ZDV/sdNVP (one study) [21]. One study stratified outcomes by time of ART initiation; SGA rates were significantly lower in women receiving TDF ART compared with non-TDF ART, initiated either preconception (adjusted odds ratio 0.3, 95% confidence interval 0.1–1.0) or during pregnancy (adjusted odds ratio 0.5, 95% confidence interval 0.3–0.8) [22]. In another study comparing SGA in women receiving only TDF ART by time of initiation, there was no significant difference in SGA when TDF ART was started preconception versus during pregnancy [23].

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Birth defects

Seven studies in HIV-infected women on ART reported on birth defects [7,10,12,13,15,19,20]. Two studies compared TDF ART with non-TDF ART regardless of trimester initiated [7,19] and four studies compared TDF ART first trimester exposure with non-TDF ART or no antiretroviral first trimester exposure [10,12,13,15]; no significant differences in birth defects were observed. The international Antiretroviral Pregnancy Registry reported 2.2% of 2779 infants with first trimester TDF exposure had birth defects, not significantly different than the 2.7% US population rate from Centers for Disease Control and Prevention surveillance; there was also no difference between first versus second/third trimester TDF exposure (2.2 versus 2.0%, respectively) [20].

Five studies in HIV-uninfected women reported on birth defects. No differences were observed in birth defects between TDF, 3TC, and no treatment in four HBV-monoinfection studies or between TDF and TDF/FTC PrEP versus placebo in the PrEP study [33–37].

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Neonatal (≤ 14 days)/infant (> 14 days) adverse events/mortality

No significant differences in adverse events were observed between TDF versus non-TDF-exposed infants in three clinical trials (two HIV trials [including the PROMISE Antepartum and Postpartum components] and one HBV-monoinfection trial) [7,9,30,36] (Table 2 ).

Two HIV ART studies reported on neonatal mortality (age <14 days) [7,19] The PROMISE trial reported higher neonatal mortality among infants born to women randomized to TDF ART (4.4%, 15/341) versus non-TDF ART (0.6%, 2/346, P = 0.001); however, there was not a significant difference between infants born to women randomized to TDF ART versus ZDV/sdNVP (3.2%, 11/349, P = 0.43) [19] The other study, also a clinical trial, did not find a significant difference in neonatal mortality with TDF ART versus non-TDF ART exposure (4.0 versus 4.4%, respectively, P = 0.40) [7] Two studies in HIV-infected women reported on infant mortality (age >14 days); neither showed an increase in infant mortality with TDF ART versus non-TDF ART or no ART through age 12–25 months [7,30]

In HIV-uninfected women, four studies in HBV-monoinfected women and one PrEP study reported on neonatal/infant mortality [33–37]. No significant differences were observed between infants exposed to TDF-containing versus control regimens in neonatal or infant mortality through age 12 months.

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Infant growth

Infant anthropometry studies primarily involve uninfected infants born to HIV-infected women who received ART during pregnancy (Table 3 ). Four studies compared birth weight-for-age z-score (WAZ), with no significant difference between infants exposed to TDF ART versus non-TDF ART [7,8,11,17]. Four studies compared birth z-scores for length-for-age (LAZ) and head circumference-for-age (HCAZ) [7,8,17,24]. No significant differences were observed between TDF ART versus non-TDF ART-exposed infants, except in one study, where TDF ART-exposed infants had better LAZ than those exposed to non-TDF ART (−1.13 versus −2.22, respectively, P = 0.03) [7]. One study compared birth LAZ by duration of in utero TDF ART exposure (<12, 12–22, and >22 weeks); LAZ at birth or 12 months did not significantly differ by exposure duration [24].

Table 3

Table 3

Table 3

Table 3

Four studies evaluated WAZ in HIV-exposed infants at age 6–12 months [8,11,18,28]. Three reported no significant WAZ differences between TDF ART versus non-TDF ART-exposed infants. One study reported better WAZ in TDF ART-exposed than non-TDF ART-exposed infants at age 12 months [28]. Three studies evaluated LAZ and HCAZ in HIV-exposed infants at age 9–12 months, with differing results [8,18,28]. One study found slightly worse LAZ and HCAZ at age 12 months among TDF ART-exposed versus non-TDF ART-exposed infants (LAZ: −0.17 versus −0.03, respectively, P = 0.04; HCAZ: +0.17 versus +0.42, P = 0.02); this study did not find differences in these parameters at birth [8]. One study reported no significant differences in either LAZ or HCAZ between TDF ART versus non-TDF ART-exposed infants [18], whereas one study showed significantly better LAZ at age 12 months with TDF ART versus non-TDF ART exposure (−1.30 versus −1.78, respectively, P < 0.001) [28].

Several additional studies in HIV-exposed and unexposed infants have evaluated growth in a variety of ways (e.g., absolute anthropometric values, proportion of children <10% percentile, or growth stratified by TDF ART exposure duration; Table 3 ). With the exception of one study, none observed significant differences between TDF ART versus non-TDF ART exposure or by duration of in utero TDF ART exposure [6–8,11,16,24,27,33,34,36,37]. One study reported lower birth and 6-month WAZ and LAZ scores in infants with TDF ART versus non-TDF-exposure, but there were only nine TDF ART-exposed infants; there was no significant difference in severe growth impairment (≥−2 z-score) by TDF exposure [27].

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Bone or renal-related studies in infants

Six studies in HIV-exposed infants and one in infants born to HIV-uninfected women in a PrEP study conducted comparative studies evaluating infant bone status in varying ways [e.g., quantitative bone ultrasound, dual-energy X-ray absorptiometry (DXA), and/or markers of bone resorption (C-terminal telopeptide of type 1 collagen) or formation (bone-specific alkaline phosphatase)] or assessed serum creatinine, calcium, or phosphorus (Table 4) [6,7,17,25,26,29,37]. There was not a significant difference in abnormal laboratory values or bone markers between TDF and non-TDF-exposed infants in four studies [7,26,29,37]. One cross-sectional study in children at median age 23 months reported slightly lower parathyroid hormone levels and urine calcium/creatinine ratio in TDF ART versus non-TDF ART-exposed children, but all values were within normal limits [6]. One study evaluated fetal femur and humerus growth by serial ultrasound in women on TDF ART stratified by duration of exposure (<10 weeks, 10–24 weeks, ≥25 weeks), and found no association between duration of in utero TDF ART exposure and change in femur and humerus length z-score (P = 0.51 and P = 0.40, respectively) [26].

Table 4

Table 4

Two studies evaluated neonatal bone mineral content (BMC) by DXA [17,25]. In a nonrandomized observational study, at median age 15 days, BMC with head was significantly lower in TDF ART versus non-TDF ART-exposed infants (adjusted difference – 5.3 g, P = 0.013), but BMC without head values were not significantly different (P = 0.15) [17]. In the randomized PROMISE trial, neonatal (age 0–21 days) whole-body BMC was compared in infants born to women randomized to TDF ART, non-TDF ART, or ZDV/sdNVP. Infants exposed to either TDF ART or non-TDF ART had significantly lower whole-body BMC than those exposed to ZDV/sdNVP (estimated difference, 9.73 g TDF-ART and 7.97 g non-TDF ART, P < 0.001 for both comparisons); however, there was not a significant difference in BMC between the two ART regimens (P = 0.41) [25].

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Maternal adverse events

In the Antepartum component of the PROMISE trial, there was no significant difference in overall grade two or higher adverse events between women randomized to TDF ART, non-TDF ART, or ZDV/sdNVP [19] (Table 5). However, grade two or higher chemistry abnormalities were significantly higher in women randomized any ART (3% TDF ART and 5% non-TDF ART) compared with ZDV/sdNVP (1%, respectively; P = 0.03 for TDF ART and 0.001 non-TDF ART); there was not a significant difference between TDF ART and non-TDF ART (P = 0.256). In the Postpartum component of PROMISE, HIV-infected breastfeeding women with CD4+ more than 350 cells/μl and their uninfected infant were randomized to receive either TDF ART (TDF/FTC/lopinavir/ritonavir) or infant NVP without maternal ART [30]. There were no significant differences in adverse events between women receiving TDF ART versus no ART during breastfeeding.

Table 5

Table 5

Three studies in HBV-monoinfected women reported on adverse events [33–35]. One study, which did not monitor unexposed women, reported on slight increase in creatinine and decline in glomerular filtration rate in women exposed to TDF, but all values were within normal limits [35]. Another study reported higher frequency of creatinine kinase elevation with TDF compared with no TDF exposure; all were grade 1/2 and the patients were asymptomatic [36].

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Maternal bone mineral content

One observational study compared spine and hip BMC T-score at 2 weeks and 9 months postpartum in breastfeeding HIV-infected women receiving either TDF ART or no ART (ZDV/sdNVP during pregnancy/intrapartum), finding no significant difference between regimens in T-score at either time point [14] (Table 5). However, in a PROMISE substudy, DXA scans were performed at one and 74 weeks postpartum in breastfeeding HIV-infected women randomized to either TDF ART or no ART; the percentage change in BMC between 1 and 74 weeks was greater in women randomized to TDF ART versus no ART for lumbar spine (percentage change −2.06% versus +1.09%, respectively, P < 0.001) and hip (percentage change −5.37% versus −3.05%, P < 0.001) [31].

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Maternal mortality

In five studies reporting on maternal mortality (two in HIV-infected and three in HBV-monoinfected women), no deaths were reported in four [19,33,34,36]; in the Postpartum PROMISE study, there were two deaths in the TDF ART arm compared with one death without ART exposure [30] (Table 5).

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Discussion

In conclusion, despite extensive in utero tenofovir exposure, as demonstrated by tenofovir detection in amniotic fluid and cord blood [39–42], data from this review indicate that TDF exposure appears generally well tolerated in terms of pregnancy outcome and infant and maternal adverse events. Studies in breastfeeding women and their infants indicate very limited exposure to tenofovir from breast milk [41,43–45]; consistent with this, the Postpartum PROMISE study, with the most extensive evaluation of TDF ART exposure in breastfeeding infants to date, reported no significant differences between infants exposed to maternal TDF ART versus no ART for any adverse outcome [30].

Most studies come from HIV-infected women receiving ART. This review, as well as other studies, observed higher rates of adverse pregnancy outcomes in HIV-infected than HIV-uninfected women even in the ART era [46]. Thus, outcomes observed with TDF ART in HIV-infected women likely provide a ‘worst case’ scenario of what might occur with TDF or TDF/FTC PrEP exposure in HIV-uninfected women. Most studies in HIV-infected women showed no adverse effects of TDF ART on the outcomes evaluated in this review.

The PROMISE trial, which enrolled HIV-infected women with CD4+ cell count more than 350 cells/μl randomized to TDF ART, non-TDF ART, or ZDV/sdNVP, found that TDF ART was associated with increased VPTD and neonatal mortality (most deaths occurring in preterm infants) compared with non-TDF ART, although there were no significant differences when compared with ZDV/sdNVP [19]. This suggests that VPTD and its associated neonatal mortality may be artificially lower in the non-TDF ART arm rather than being abnormally high in the TDF ART arm. In contrast to PROMISE, PTD was not higher with TDF use in 10 other comparative studies, including 4606 women (4066 HIV-infected and 540 HIV-uninfected) [7,11,21,22,33–38]. Neonatal mortality was not higher with TDF ART exposure in the one other study reporting this parameter, and neonatal/infant mortality was not elevated with TDF exposure in seven other studies [8,31,33–38].

There are fewer studies of TDF in HIV-uninfected women. In HIV-uninfected women with HBV monoinfection, TDF given as a single drug, is usually initiated in the third trimester of pregnancy and stopped 1–2 months postpartum. In studies in HBV-monoinfected pregnant women, no significant differences in any outcome were observed between TDF, 3TC, and no drug exposure, and TDF was shown to reduce perinatal HBV transmission [33–37]. The data from the two PrEP studies in HIV-uninfected women are similarly reassuring, although in these trials PrEP was discontinued after pregnancy was recognized (generally at 1 to 2-month gestation). Although the VOICE study is confounded by the poor adherence to PrEP, this was not true for the Partners PrEP study where adherence was excellent, particularly in women receiving PrEP around the periconception period [37,38,47]. Some of the planned PrEP demonstration projects are allowing women to continue PrEP during pregnancy and lactation, which will provide additional data on infant outcomes.

Data on infant growth, bone development, and renal function were similarly reassuring. The most recent infant DXA study from PROMISE suggests that ART itself may be associated with some decrement in neonatal BMC, but this was not specific for TDF, as non-TDF ART showed a similar decrement [25]. Further study is needed to see if these differences persist and if clinically relevant.

Few studies provided detailed reports on maternal adverse event. Maternal mortality was very low in all studies. An increase in chemistry adverse events was observed with ART compared with ZDV/sdNVP in the PROMISE study, but was not TDF specific [19]; the Postpartum PROMISE trial did not find any difference in adverse events between breastfeeding women receiving TDF ART versus no ART during a median 15-months of breastfeeding [30]. No significant effects of TDF exposure on renal function were noted in studies reporting on this parameter [19,20,33–36]. In the PROMISE substudy, a significant difference in BMC was observed through 74 weeks in women randomized to TDF ART versus no ART; whether this resolves after breastfeeding is discontinued is not known [31]. Studies of BMC in young African women receiving TDF PrEP have shown small but reversible decreases in hip and spine BMC [48].

In conclusion, in the HIV-infected population, TDF ART appears generally similar to other ART regimens when examining maternal, pregnancy, and growth outcomes. These data, combined with limited data in HIV-uninfected women, appear reassuring in terms of the safety of using PrEP by pregnant/lactating HIV-uninfected women. Young women in sub-Saharan Africa, particularly if pregnant or breastfeeding, experience some of the highest HIV incidence rates globally. PrEP use by pregnant and breastfeeding women can provide dual benefits, reducing the risk of HIV acquisition in the mother–infant pair. A cost-effectiveness analysis found PrEP provision to pregnant/breastfeeding HIV-uninfected but at-risk women in sub-Saharan Africa to be cost-effective and outweighs even a substantially increased PTD risk [49]. Although additional surveillance is important, given the available safety data, the benefits of PrEP use for prevention by pregnant/lactating women at high risk of HIV acquisition (and its accompanying increased risk of mother-to-child HIV transmission) appear to far outweigh the potential risks of fetal, infant, and maternal TDF exposure [50].

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Acknowledgements

R.C.B. and I.M. conceptualized the need for the review and provided significant input to the drafting of the manuscript; L.M.M. conducted the review and prepared the manuscript.

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Conflicts of interest

There are no conflicts of interest.

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Keywords:

breastfeeding; drug safety in pregnancy and breastfeeding; preexposure prophylaxis; pregnancy; tenofovir disoproxil fumarate

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